Different molecular alterations have been described in colorectal cancer. Among them, the irregular activation of protein kinases plays a central role. Several protein kinases have been associated with the initiation, maintenance and progression of this tumor type, including receptor tyrosine kinases (RTK) or downstream mediators. An example is the aberrant activation of the Epidermal Growth Factor Receptor (EGFR) and the Vascular Endothelial Growth Factor (VEGFR) in colon cancer. In addition, agents against them have reached a clinical setting, thus demonstrating clinical benefit.
Taken in consideration that solid tumors, and in particular colorectal cancers, are heterogeneous diseases, the understanding of the kinase profile of this disease could help in the selection of relevant therapeutic strategies. This approach has been explored recently in prostate cancer by evaluating the activated state of different kinases from several patients and metastatic sites, observing a high inter-patient heterogeneity but similar activation within metastatic sites in the same patient.
This data, in addition to the increased therapeutic efficacy of the concomitant inhibition of several kinases compared with single kinase inhibition, suggests that the identification of tyrosine kinase inhibitors with a broad inhibitory effect can present a higher antitumor effect against colorectal cancer.
Several signaling routes are clearly activated in colon cancer and linked with oncogenic transformation. Some of them include the PI3K/mTOR pathway, the MAPK kinase route, angiogenesis pathways or routes associated with migration such as the FAK family of kinases. The concomitant targeting of some of these functions to concomitantly inhibit progression, migration or survival could have a broader effect. Thus, it is a problem of the present invention to explore the kinase profile of primary colorectal tumors and identify tyrosine kinase inhibitors with anti-proliferative effect by pharmacological screening.
Moreover, it is the problem of the present invention to provide improved means of preventing and/or treating colorectal cancer, but also provides an anti-proliferative, tumor-specific effect, such that it does not exhibit adverse side effects.